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  • 제23권1호
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  • Pages.6.1-6.24
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  • 2023
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Gut Microbial Metabolites on Host Immune Responses in Health and Disease

  • Jong-Hwi Yoon (Department of Microbiology and Immunology, Yonsei University College of Medicine) ;
  • Jun-Soo Do (Department of Microbiology and Immunology, Yonsei University College of Medicine) ;
  • Priyanka Velankanni (Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Choong-Gu Lee (Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Ho-Keun Kwon (Department of Microbiology and Immunology, Yonsei University College of Medicine)
  • 투고 : 2022.12.27
  • 심사 : 2023.02.13
  • 발행 : 2023.02.28
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초록

Intestinal microorganisms interact with various immune cells and are involved in gut homeostasis and immune regulation. Although many studies have discussed the roles of the microorganisms themselves, interest in the effector function of their metabolites is increasing. The metabolic processes of these molecules provide important clues to the existence and function of gut microbes. The interrelationship between metabolites and T lymphocytes in particular plays a significant role in adaptive immune functions. Our current review focuses on 3 groups of metabolites: short-chain fatty acids, bile acids metabolites, and polyamines. We collated the findings of several studies on the transformation and production of these metabolites by gut microbes and explained their immunological roles. Specifically, we summarized the reports on changes in mucosal immune homeostasis represented by the Tregs and Th17 cells balance. The relationship between specific metabolites and diseases was also analyzed through latest studies. Thus, this review highlights microbial metabolites as the hidden treasure having potential diagnostic markers and therapeutic targets through a comprehensive understanding of the gut-immune interaction.

키워드

과제정보

This study was supported by grants from the Korea Health Technology R&D project through the Korea Health Industry Development Institute (HV20C0172 and HV22C0246), "Team Science Award" of Yonsei University College of Medicine (6-2021-0194), National Research Foundation of Korea (2021R1C1C1007040), and an intramural grant of Korea Institute of Science and Technology (2Z06822). Figures have been created with BioRender.

참고문헌

  1. Yang W, Cong Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol 2021;18:866-877.
  2. Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 2016;165:1332-1345.
  3. van der Hee B, Wells JM. Microbial regulation of host physiology by short-chain fatty acids. Trends Microbiol 2021;29:700-712.
  4. Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 2015;64:1744-1754.
  5. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A 2008;105:16767-16772.
  6. Park JW, Kim HY, Kim MG, Jeong S, Yun CH, Han SH. Short-chain fatty acids inhibit staphylococcal lipoprotein-induced nitric oxide production in murine macrophages. Immune Netw 2019;19:e9.
  7. Zhu Z, Zhu B, Hu C, Liu Y, Wang X, Zhang J, Wang F, Zhu M. Short-chain fatty acids as a target for prevention against food allergy by regulatory T cells. JGH Open 2019;3:190-195.
  8. Zhou L, Zhang M, Wang Y, Dorfman RG, Liu H, Yu T, Chen X, Tang D, Xu L, Yin Y, et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. Inflamm Bowel Dis 2018;24:1926-1940.
  9. Huang J, Pearson JA, Peng J, Hu Y, Sha S, Xing Y, Huang G, Li X, Hu F, Xie Z, et al. Gut microbial metabolites alter IgA immunity in type 1 diabetes. JCI Insight 2020;5:e135718.
  10. Juanola O, Pinero P, Gomez-Hurtado I, Caparros E, Garcia-Villalba R, Marin A, Zapater P, Tarin F, Gonzalez-Navajas JM, Tomas-Barberan FA, et al. Regulatory T cells restrict permeability to bacterial antigen translocation and preserve short-chain fatty acids in experimental cirrhosis. Hepatol Commun 2018;2:1610-1623.
  11. Hu M, Eviston D, Hsu P, Marino E, Chidgey A, Santner-Nanan B, Wong K, Richards JL, Yap YA, Collier F, et al. Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia. Nat Commun 2019;10:3031.
  12. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013;54:2325-2340.
  13. Rey FE, Faith JJ, Bain J, Muehlbauer MJ, Stevens RD, Newgard CB, Gordon JI. Dissecting the in vivo metabolic potential of two human gut acetogens. J Biol Chem 2010;285:22082-22090.
  14. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014;12:661-672.
  15. Chiang JY. Bile acid metabolism and signaling. Compr Physiol 2013;3:1191-1212.
  16. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-174.
  17. Molinaro A, Wahlstrom A, Marschall HU. Role of bile acids in metabolic control. Trends Endocrinol Metab 2018;29:31-41.
  18. Fuchs CD, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022;19:432-450.
  19. Di Ciaula A, Garruti G, Lunardi Baccetto R, Molina-Molina E, Bonfrate L, Wang DQ, Portincasa P. Bile acid physiology. Ann Hepatol 2017;16:s4-s14.
  20. Guzior DV, Quinn RA. Review: microbial transformations of human bile acids. Microbiome 2021;9:140.
  21. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-235.
  22. Chiang JY. Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. Hepatology 2015;62:1315-1317.
  23. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016;7:22-39.
  24. Ridlon JM, Hylemon PB. Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium. J Lipid Res 2012;53:66-76.
  25. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006;47:241-259.
  26. Paik D, Yao L, Zhang Y, Bae S, D'Agostino GD, Zhang M, Kim E, Franzosa EA, Avila-Pacheco J, Bisanz JE, et al. Human gut bacteria produce TH17-modulating bile acid metabolites. Nature 2022;603:907-912.
  27. Li W, Hang S, Fang Y, Bae S, Zhang Y, Zhang M, Wang G, McCurry MD, Bae M, Paik D, et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host Microbe 2021;29:1366-1377.e9.
  28. Aguirre AM, Yalcinkaya N, Wu Q, Swennes A, Tessier ME, Roberts P, Miyajima F, Savidge T, Sorg JA. Bile acid-independent protection against Clostridioides difficile infection. PLoS Pathog 2021;17:e1010015.
  29. Urdaneta V, Casadesus J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts. Front Med (Lausanne) 2017;4:163.
  30. Li J, Meng Y, Wu X, Sun Y. Polyamines and related signaling pathways in cancer. Cancer Cell Int 2020;20:539.
  31. Larque E, Sabater-Molina M, Zamora S. Biological significance of dietary polyamines. Nutrition 2007;23:87-95.
  32. Thomas T, Thomas TJ. Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci 2001;58:244-258.
  33. Nakanishi S, Cleveland JL. Polyamine homeostasis in development and disease. Med Sci (Basel) 2021;9:28.
  34. Moinard C, Cynober L, de Bandt JP. Polyamines: metabolism and implications in human diseases. Clin Nutr 2005;24:184-197.
  35. Tofalo R, Cocchi S, Suzzi G. Polyamines and gut microbiota. Front Nutr 2019;6:16.
  36. Igarashi K, Kashiwagi K. Characteristics of cellular polyamine transport in prokaryotes and eukaryotes. Plant Physiol Biochem 2010;48:506-512.
  37. Sugiyama Y, Nara M, Sakanaka M, Gotoh A, Kitakata A, Okuda S, Kurihara S. Comprehensive analysis of polyamine transport and biosynthesis in the dominant human gut bacteria: potential presence of novel polyamine metabolism and transport genes. Int J Biochem Cell Biol 2017;93:52-61.
  38. Burrell M, Hanfrey CC, Murray EJ, Stanley-Wall NR, Michael AJ. Evolution and multiplicity of arginine decarboxylases in polyamine biosynthesis and essential role in Bacillus subtilis biofilm formation. J Biol Chem 2010;285:39224-39238.
  39. Suarez C, Espariz M, Blancato VS, Magni C. Expression of the agmatine deiminase pathway in Enterococcus faecalis is activated by the AguR regulator and repressed by CcpA and PTSMan systems. PLoS One 2013;8:e76170.
  40. Hanfrey CC, Pearson BM, Hazeldine S, Lee J, Gaskin DJ, Woster PM, Phillips MA, Michael AJ. Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. J Biol Chem 2011;286:43301-43312.
  41. Nakamura A, Ooga T, Matsumoto M. Intestinal luminal putrescine is produced by collective biosynthetic pathways of the commensal microbiome. Gut Microbes 2019;10:159-171.
  42. Kitada Y, Muramatsu K, Toju H, Kibe R, Benno Y, Kurihara S, Matsumoto M. Bioactive polyamine production by a novel hybrid system comprising multiple indigenous gut bacterial strategies. Sci Adv 2018;4:eaat0062.
  43. Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T, Sawaki E, Muramatsu K, Nakamura A, Yamashita A, Kitada Y, et al. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci Rep 2014;4:4548.
  44. Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One 2011;6:e23652.
  45. Matsumoto M, Kitada Y, Naito Y. Endothelial function is improved by inducing microbial polyamine production in the gut: a randomized placebo-controlled trial. Nutrients 2019;11:11.
  46. Chevalier C, Kieser S, Colakoglu M, Hadadi N, Brun J, Rigo D, Suarez-Zamorano N, Spiljar M, Fabbiano S, Busse B, et al. Warmth prevents bone loss through the gut microbiota. Cell Metab 2020;32:575-590.e7.
  47. Zhao Q, Huang JF, Cheng Y, Dai MY, Zhu WF, Yang XW, Gonzalez FJ, Li F. Polyamine metabolism links gut microbiota and testicular dysfunction. Microbiome 2021;9:224.
  48. Noack J, Kleessen B, Proll J, Dongowski G, Blaut M. Dietary guar gum and pectin stimulate intestinal microbial polyamine synthesis in rats. J Nutr 1998;128:1385-1391.
  49. Noack J, Dongowski G, Hartmann L, Blaut M. The human gut bacteria Bacteroides thetaiotaomicron and Fusobacterium varium produce putrescine and spermidine in cecum of pectin-fed gnotobiotic rats. J Nutr 2000;130:1225-1231.
  50. Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, et al. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes 2020;12:1-19.
  51. Lin MY, de Zoete MR, van Putten JP, Strijbis K. Redirection of epithelial immune responses by short-chain fatty acids through inhibition of histone deacetylases. Front Immunol 2015;6:554.
  52. Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, Franchini F, Chomka A, Ilott NE, Johnston DG, Pires E, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 2019;50:432-445.e7.
  53. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569-573.
  54. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446-450.
  55. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013;504:451-455.
  56. Antunes KH, Fachi JL, de Paula R, da Silva EF, Pral LP, Dos Santos AA, Dias GB, Vargas JE, Puga R, Mayer FQ, et al. Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nat Commun 2019;10:3273.
  57. Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, Ubags N, Fajas L, Nicod LP, Marsland BJ. Dietary fiber confers protection against flu by shaping Ly6c-  patrolling monocyte hematopoiesis and CD8+  T cell metabolism. Immunity 2018;48:992-1005.e8.
  58. Sencio V, Barthelemy A, Tavares LP, Machado MG, Soulard D, Cuinat C, Queiroz-Junior CM, Noordine ML, Salome-Desnoulez S, Deryuter L, et al. Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production. Cell Reports 2020;30:2934-2947.e6.
  59. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12:4077.
  60. Yang W, Yu T, Huang X, Bilotta AJ, Xu L, Lu Y, Sun J, Pan F, Zhou J, Zhang W, et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat Commun 2020;11:4457.
  61. Sanchez HN, Moroney JB, Gan H, Shen T, Im JL, Li T, Taylor JR, Zan H, Casali P. B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids. Nat Commun 2020;11:60.
  62. Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, Hengstler JG. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017;65:722-738.
  63. Song P, Zhang Y, Klaassen CD. Dose-response of five bile acids on serum and liver bile acid concentrations and hepatotoxicty in mice. Toxicol Sci 2011;123:359-367.
  64. Galle PR, Theilmann L, Raedsch R, Otto G, Stiehl A. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 1990;12:486-491.
  65. Hofmann AF, Roda A. Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J Lipid Res 1984;25:1477-1489.
  66. Fiorucci S, Zampella A, Ricci P, Distrutti E, Biagioli M. Immunomodulatory functions of FXR. Mol Cell Endocrinol 2022;551:111650.
  67. Zhou J, Cui S, He Q, Guo Y, Pan X, Zhang P, Huang N, Ge C, Wang G, Gonzalez FJ, et al. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun 2020;11:240.
  68. Zhang MY, Luo M, Wang JP. FXR expression in rats of hilar cholangiocarcinoma. Sci Rep 2022;12:8741.
  69. Miyazaki T, Shirakami Y, Mizutani T, Maruta A, Ideta T, Kubota M, Sakai H, Ibuka T, Genovese S, Fiorito S, et al. Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis. Sci Rep 2021;11:492.
  70. Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 2009;183:6251-6261.
  71. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998;92:73-82.
  72. Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 2001;98:3369-3374.
  73. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002;298:714-719.
  74. Shi Y, Su W, Zhang L, Shi C, Zhou J, Wang P, Wang H, Shi X, Wei S, Wang Q, et al. TGR5 regulates macrophage inflammation in nonalcoholic steatohepatitis by modulating NLRP3 inflammasome activation. Front Immunol 2021;11:609060.
  75. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011;54:1263-1272.
  76. Portincasa P, Di Ciaula A, Garruti G, Vacca M, De Angelis M, Wang DQ. Bile acids and gpbar-1: dynamic interaction involving genes, environment and gut microbiome. Nutrients 2020;12:3790.
  77. Nagahashi M, Yuza K, Hirose Y, Nakajima M, Ramanathan R, Hait NC, Hylemon PB, Zhou H, Takabe K, Wakai T. The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases. J Lipid Res 2016;57:1636-1643.
  78. Campbell C, Marchildon F, Michaels AJ, Takemoto N, van der Veeken J, Schizas M, Pritykin Y, Leslie CS, Intlekofer AM, Cohen P, et al. FXR mediates T cell-intrinsic responses to reduced feeding during infection. Proc Natl Acad Sci U S A 2020;117:33446-33454.
  79. Wilson A, Almousa A, Teft WA, Kim RB. Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn's disease. Sci Rep 2020;10:1866.
  80. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60:463-472.
  81. Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, Santucci L, Fiorucci S. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol 2009;183:6657-6666.
  82. Guillot A, Guerri L, Feng D, Kim SJ, Ahmed YA, Paloczi J, He Y, Schuebel K, Dai S, Liu F, et al. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury. J Clin Invest 2021;131:e132305.
  83. Wammers M, Schupp AK, Bode JG, Ehlting C, Wolf S, Deenen R, Kohrer K, Haussinger D, Graf D. Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids. Sci Rep 2018;8:255.
  84. Biagioli M, Carino A, Fiorucci C, Marchiano S, Di Giorgio C, Roselli R, Magro M, Distrutti E, Bereshchenko O, Scarpelli P, et al. Gpbar1 functions as gatekeeper for liver NKT cells and provides counterregulatory signals in mouse models of immune-mediated hepatitis. Cell Mol Gastroenterol Hepatol 2019;8:447-473.
  85. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, Baldelli F, Donini A, Fiorucci S. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 2011;6:e25637.
  86. Biagioli M, Carino A, Cipriani S, Francisci D, Marchiano S, Scarpelli P, Sorcini D, Zampella A, Fiorucci S. The bile acid receptor gpbar1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol 2017;199:718-733.
  87. Hu J, Wang C, Huang X, Yi S, Pan S, Zhang Y, Yuan G, Cao Q, Ye X, Li H. Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. Cell Reports 2021;36:109726.
  88. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84.
  89. Ding C, Hong Y, Che Y, He T, Wang Y, Zhang S, Wu J, Xu W, Hou J, Hao H, et al. Bile acid restrained T cell activation explains cholestasis aggravated hepatitis B virus infection. FASEB J 2022;36:e22468.
  90. Pols TW, Puchner T, Korkmaz HI, Vos M, Soeters MR, de Vries CJ. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor. PLoS One 2017;12:e0176715.
  91. Shi Z, Wu X, Wu CY, Singh SP, Law T, Yamada D, Huynh M, Liakos W, Yang G, Farber JM, et al. Bile acids improve psoriasiform dermatitis through inhibition of IL-17A expression and CCL20-CCR6-mediated trafficking of T cells. J Invest Dermatol 2022;142:1381-1390.e11.
  92. Song X, Sun X, Oh SF, Wu M, Zhang Y, Zheng W, Geva-Zatorsky N, Jupp R, Mathis D, Benoist C, et al. Microbial bile acid metabolites modulate gut RORγ+  regulatory T cell homeostasis. Nature 2020;577:410-415.
  93. Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, Ha S, Nelson BN, Kelly SP, Wu L, et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 2019;576:143-148.
  94. Campbell C, McKenney PT, Konstantinovsky D, Isaeva OI, Schizas M, Verter J, Mai C, Jin WB, Guo CJ, Violante S, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 2020;581:475-479.
  95. Banerji R, Kanojiya P, Patil A, Saroj SD. Polyamines in the virulence of bacterial pathogens of respiratory tract. Mol Oral Microbiol 2021;36:1-11.
  96. Rollins-Smith LA, Ruzzini AC, Fites JS, Reinert LK, Hall EM, Joosse BA, Ravikumar VI, Huebner MI, Aka A, Kehs MH, et al. Metabolites involved in immune evasion by Batrachochytrium dendrobatidis include the polyamine spermidine. Infect Immun 2019;87:e00035-19.
  97. Firpo MR, Mastrodomenico V, Hawkins GM, Prot M, Levillayer L, Gallagher T, Simon-Loriere E, Mounce BC. Targeting polyamines inhibits coronavirus infection by reducing cellular attachment and entry. ACS Infect Dis 2021;7:1423-1432.
  98. Hardbower DM, Asim M, Luis PB, Singh K, Barry DP, Yang C, Steeves MA, Cleveland JL, Schneider C, Piazuelo MB, et al. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc Natl Acad Sci U S A 2017;114:E751-E760.
  99. Puleston DJ, Simon AK. New roles for autophagy and spermidine in T cells. Microb Cell 2015;2:91-93.
  100. Rossi G, Cerquetella M, Scarpona S, Pengo G, Fettucciari K, Bassotti G, Jergens AE, Suchodolski JS. Effects of probiotic bacteria on mucosal polyamines levels in dogs with IBD and colonic polyps: a preliminary study. Benef Microbes 2018;9:247-255.
  101. Puntambekar SS, Davis DS, Hawel L 3rd, Crane J, Byus CV, Carson MJ. LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent. Brain Behav Immun 2011;25:629-639.
  102. Zhang M, Caragine T, Wang H, Cohen PS, Botchkina G, Soda K, Bianchi M, Ulrich P, Cerami A, Sherry B, et al. Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med 1997;185:1759-1768.
  103. Cao W, Wu X, Jia G, Zhao H, Chen X, Wu C, Tang J, Wang J, Cai J, Liu G. New insights into the role of dietary spermine on inflammation, immune function and related-signalling molecules in the thymus and spleen of piglets. Arch Anim Nutr 2017;71:175-191.
  104. Zhu S, Ashok M, Li J, Li W, Yang H, Wang P, Tracey KJ, Sama AE, Wang H. Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. Mol Med 2009;15:275-282.
  105. Li G, Ding H, Yu X, Meng Y, Li J, Guo Q, Zhou H, Shen N. Spermidine suppresses inflammatory DC function by activating the FOXO3 pathway and counteracts autoimmunity. iScience 2020;23:100807.
  106. Puleston DJ, Buck MD, Klein Geltink RI, Kyle RL, Caputa G, O'Sullivan D, Cameron AM, Castoldi A, Musa Y, Kabat AM, et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab 2019;30:352-363.e8.
  107. Jeong JW, Cha HJ, Han MH, Hwang SJ, Lee DS, Yoo JS, Choi IW, Kim S, Kim HS, Kim GY, et al. Spermidine protects against oxidative stress in inflammation models using macrophages and zebrafish. Biomol Ther (Seoul) 2018;26:146-156.
  108. Zhang H, Alsaleh G, Feltham J, Sun Y, Napolitano G, Riffelmacher T, Charles P, Frau L, Hublitz P, Yu Z, et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol Cell 2019;76:110-125.e9.
  109. Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J. Microbiome dependent regulation of Tregs and Th17 cells in mucosa. Front Immunol 2019;10:426.
  110. Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 2003;100:8412-8417.
  111. Suzuki T, Yoshida S, Hara H. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 2008;100:297-305.
  112. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014;40:128-139.
  113. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003;278:11312-11319.
  114. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282-1286.
  115. Kang HJ, Kim GC, Lee CG, Park S, Sharma G, Verma R, Im SH, Kwon HK. Probiotics-derived metabolite ameliorates skin allergy by promoting differentiation of FOXP3+ regulatory T cells. J Allergy Clin Immunol 2021;147:1517-1521.
  116. Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey FE, Denu JM. Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol Cell 2016;64:982-992.
  117. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 1978;14:105-113.
  118. Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim CH. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 2015;8:80-93.
  119. Coutzac C, Jouniaux JM, Paci A, Schmidt J, Mallardo D, Seck A, Asvatourian V, Cassard L, Saulnier P, Lacroix L, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun 2020;11:2168.
  120. Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, Kabat AM, Kaminski MM, Stanckzak M, Weiss HJ, Grzes KM, et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 2021;184:4186-4202.e20.
  121. Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 2021;184:4168-4185.e21.
  122. Mondanelli G, Bianchi R, Pallotta MT, Orabona C, Albini E, Iacono A, Belladonna ML, Vacca C, Fallarino F, Macchiarulo A, et al. A relay pathway between arginine and tryptophan metabolism confers immunosuppressive properties on dendritic cells. Immunity 2017;46:233-244.
  123. Carriche GM, Almeida L, Stuve P, Velasquez L, Dhillon-LaBrooy A, Roy U, Lindenberg M, Strowig T, Plaza-Sirvent C, Schmitz I, et al. Regulating T-cell differentiation through the polyamine spermidine. J Allergy Clin Immunol 2021;147:335-348.e11.
  124. Trapecar M, Communal C, Velazquez J, Maass CA, Huang YJ, Schneider K, Wright CW, Butty V, Eng G, Yilmaz O, et al. Gut-liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids. Cell Syst 2020;10:223-239.e9.
  125. Behary J, Amorim N, Jiang XT, Raposo A, Gong L, McGovern E, Ibrahim R, Chu F, Stephens C, Jebeili H, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun 2021;12:187.
  126. Du HX, Yue SY, Niu D, Liu C, Zhang LG, Chen J, Chen Y, Guan Y, Hua XL, Li C, et al. Gut microflora modulates Th17/Treg cell differentiation in experimental autoimmune prostatitis via the short-chain fatty acid propionate. Front Immunol 2022;13:915218.
  127. Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P, Christl S, Richter F, Dusel G, Kasper H. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992;103:51-56.
  128. Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 1989;320:23-28.
  129. Segain JP, Raingeard de la Bletiere D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottiere HM, Galmiche JP. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn's disease. Gut 2000;47:397-403.
  130. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 2007;104:979-984.
  131. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-63.
  132. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016;165:111-124.
  133. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Backhed F, Mithieux G. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014;156:84-96.
  134. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 2016;165:1762-1775.
  135. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014;20:159-166.
  136. Ye Z, Zhang N, Wu C, Zhang X, Wang Q, Huang X, Du L, Cao Q, Tang J, Zhou C, et al. A metagenomic study of the gut microbiome in Behcet's disease. Microbiome 2018;6:135.
  137. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018;360:eaan5931.
  138. Lee CK, Jeong SH, Jang C, Bae H, Kim YH, Park I, Kim SK, Koh GY. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science 2019;363:644-649.
  139. Fu T, Coulter S, Yoshihara E, Oh TG, Fang S, Cayabyab F, Zhu Q, Zhang T, Leblanc M, Liu S, et al. FXR regulates intestinal cancer stem cell proliferation. Cell 2019;176:1098-1112.e18.
  140. Fiorucci S, Di Giorgio C, Distrutti E. Obeticholic acid: an update of its pharmacological activities in liver disorders. Handb Exp Pharmacol 2019;256:283-295.
  141. Vang S, Longley K, Steer CJ, Low WC. The unexpected uses of urso- and tauroursodeoxycholic acid in the treatment of non-liver diseases. Glob Adv Health Med 2014;3:58-69.
  142. Daruich A, Jaworski T, Henry H, Zola M, Youale J, Parenti L, Naud MC, Delaunay K, Bertrand M, Berdugo M, et al. Oral ursodeoxycholic acid crosses the blood retinal barrier in patients with retinal detachment and protects against retinal degeneration in an ex vivo model. Neurotherapeutics 2021;18:1325-1338.
  143. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, et al. Farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-965.
  144. Weingarden AR, Chen C, Zhang N, Graiziger CT, Dosa PI, Steer CJ, Shaughnessy MK, Johnson JR, Sadowsky MJ, Khoruts A. Ursodeoxycholic acid inhibits clostridium difficile spore germination and vegetative growth, and prevents recurrence of ileal pouchitis associated with the infection. J Clin Gastroenterol 2016;50:624-630.
  145. Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, Jorgensen R, Petz J, Keach J, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808-814.
  146. Mousa OY, Juran BD, McCauley BM, Vesterhus MN, Folseraas T, Turgeon CT, Ali AH, Schlicht EM, Atkinson EJ, Hu C, et al. Bile acid profiles in primary sclerosing cholangitis and their ability to predict hepatic decompensation. Hepatology 2021;74:281-295.
  147. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Pares A, Mason A, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018;67:1890-1902.
  148. Liu R, Li X, Ma H, Yang Q, Shang Q, Song L, Zheng Z, Zhang S, Pan Y, Huang P, et al. Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy. Free Radic Biol Med 2020;161:339-350.
  149. Baier J, Gansbauer M, Giessler C, Arnold H, Muske M, Schleicher U, Lukassen S, Ekici A, Rauh M, Daniel C, et al. Arginase impedes the resolution of colitis by altering the microbiome and metabolome. J Clin Invest 2020;130:5703-5720.
  150. Guo X, Harada C, Namekata K, Kimura A, Mitamura Y, Yoshida H, Matsumoto Y, Harada T. Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis. Invest Ophthalmol Vis Sci 2011;52:2696-2703.
  151. Yang Q, Zheng C, Cao J, Cao G, Shou P, Lin L, Velletri T, Jiang M, Chen Q, Han Y, et al. Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages. Cell Death Differ 2016;23:1850-1861.
  152. Kim HA, Lee HS, Shin TH, Jung JY, Baek WY, Park HJ, Lee G, Paik MJ, Suh CH. Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever. Lupus 2018;27:930-938.
  153. Wang X, Stearns NA, Li X, Pisetsky DS. The effect of polyamines on the binding of anti-DNA antibodies from patients with SLE and normal human subjects. Clin Immunol 2014;153:94-103.
  154. Furumitsu Y, Yukioka K, Kojima A, Yukioka M, Shichikawa K, Ochi T, Matsui-Yuasa I, Otani S, Nishizawa Y, Morii H. Levels of urinary polyamines in patients with rheumatoid arthritis. J Rheumatol 1993;20:1661-1665.
  155. Yukioka K, Wakitani S, Yukioka M, Furumitsu Y, Shichikawa K, Ochi T, Goto H, Matsui-Yuasa I, Otani S, Nishizawa Y, et al. Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis. J Rheumatol 1992;19:689-692.
  156. Iezaki T, Hinoi E, Yamamoto T, Ishiura R, Ogawa S, Yoneda Y. Amelioration by the natural polyamine spermine of cartilage and bone destruction in rats with collagen-induced arthritis. J Pharmacol Sci 2012;119:107-111.
  157. Karouzakis E, Gay RE, Gay S, Neidhart M. Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2012;64:1809-1817.
  158. Klein K, Gay S. Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol 2015;27:76-82.
  159. Moreno B, Fernandez-Diez B, Di Penta A, Villoslada P. Preclinical studies of methylthioadenosine for the treatment of multiple sclerosis. Mult Scler 2010;16:1102-1108.
  160. Moreno B, Hevia H, Santamaria M, Sepulcre J, Munoz J, Garcia-Trevijano ER, Berasain C, Corrales FJ, Avila MA, Villoslada P. Methylthioadenosine reverses brain autoimmune disease. Ann Neurol 2006;60:323-334.
  161. Wu R, Chen X, Kang S, Wang T, Gnanaprakasam JR, Yao Y, Liu L, Fan G, Burns MR, Wang R. De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function. Sci Adv 2020;6:eabc4275.
  162. Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 2011;6:e25792.
  163. Bottcher MF, Nordin EK, Sandin A, Midtvedt T, Bjorksten B. Microflora-associated characteristics in faeces from allergic and nonallergic infants. Clin Exp Allergy 2000;30:1590-1596.
  164. Sinha SR, Haileselassie Y, Nguyen LP, Tropini C, Wang M, Becker LS, Sim D, Jarr K, Spear ET, Singh G, et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020;27:659-670.e5.
  165. Bazzari FH, Abdallah DM, El-Abhar HS. Chenodeoxycholic acid ameliorates alcl3-induced Alzheimer's disease neurotoxicity and cognitive deterioration via enhanced insulin signaling in rats. Molecules 2019;24:1992.
  166. Hu J, Wang C, Huang X, Yi S, Pan S, Zhang Y, Yuan G, Cao Q, Ye X, Li H. Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. Cell Reports 2021;36:109726.
  167. Liu H, Tian R, Wang H, Feng S, Li H, Xiao Y, Luan X, Zhang Z, Shi N, Niu H, et al. Gut microbiota from coronary artery disease patients contributes to vascular dysfunction in mice by regulating bile acid metabolism and immune activation. J Transl Med 2020;18:382.
  168. Miko E, Vida A, Kovacs T, Ujlaki G, Trencsenyi G, Marton J, Sari Z, Kovacs P, Boratko A, Hujber Z, et al. Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg 2018;1859:958-974.
  169. Lepercq P, Gerard P, Beguet F, Raibaud P, Grill JP, Relano P, Cayuela C, Juste C. Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces. FEMS Microbiol Lett 2004;235:65-72.
  170. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016;7:22-39.
  171. Zhang H, Xu H, Zhang C, Tang Q, Bi F. Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis. Cell Death Dis 2021;7:207.
  172. Mueller M, Thorell A, Claudel T, Jha P, Koefeler H, Lackner C, Hoesel B, Fauler G, Stojakovic T, Einarsson C, et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 2015;62:1398-1404.